Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1)([O-])=O.[ClH:16]>C(O)C.C(OCC)(=O)C.O.[Pd]>[ClH:16].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cn2cncn2)cc1
Yield: 100 %

Procedure:
A solution of 1-(4-nitrophenyl)methyl-1,2,4-triazole (10.0 g, 49 mmol) in ethanol (50 ml), ethyl acetate (50 ml), 5N HCl (10 ml) and water (10 ml) was hydrogenated over 10% Pd/C (1.0 g) at 40 p.s.i., in a Parr apparatus, until an uptake of 188 p.s.i., had been observed (approx 10 mins). The catalyst was removed by filtration through hyflo and the solvent removed under vacuum. The residue was azeotroped with ethanol (×2) to give the titleamine hydrochloride (10.6 g, 100%). δ (360 MHz, D2O) 5.53 (2H, s, CH2), 7.37-7.48 (4H, m, Ar-H), 8.12 (1H, s, Ar-H), 8.66 (1H, s, Ar-H).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([CH3:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([S:25]([O:28]CC)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:1]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][C:4]([C:7]2[N+:8]([CH2:19][CH3:20])=[C:9]([CH3:12])[S:10][CH:11]=2)=[CH:3][CH:2]=1.[CH3:31][C:19]1[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1nc(-c2ccc(-c3ccccc3)cc2)cs1
Product: CC[n+]1c(-c2ccc(-c3ccccc3)cc2)csc1C
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
4-(Biphenyl-4-yl)-2-methyl-thiazole (9.8 pbw) and ethyl p-toluenesulfonate (8.6 pbw) are stirred for 3 hours at 180° C. The hot mixture is poured onto acetone and further processed as described in Preparation Example 5(a).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1.C(N(CC)CC)C.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[S:36]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][O:9]1)([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(CCCCOC1CCCCO1)CCCc1cccnc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(CCCCOC2CCCCO2)CCCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.405 g (1.3 mmol) 5-hydroxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)octane in 8 ml methylene chloride is added a few crystals of 4-dimethylaminopyridine followed by 0.5 ml (3.6 mmol) triethylamine and 0.5 g (2.6 mmol) p-toluenesulfonyl chloride. The reaction mixture is stirred at room temperature for 18 h and then diluted with ether. The ether layer is washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated to give an amber oil which is purified by chromatography over silica gel using ether/ethycetate (4:1) as eluent to yield 5-tosyloxy-8-(3-pyridyl)-1-(2-tetrahydropyranyloxy)-octane; NMR (CDCl3): delta 7.9 (d,2H), 7.4 (d,2H), 2.45 (s,3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH:8]=[CH:9]2)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: COc1cc(C#N)ccc1CBr
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(C#N)ccc1Cn1ccc2ccc([N+](=O)[O-])cc21
Yield: 78 %

Procedure:
6-Nitroindole as alkylated with 4-bromomethyl-3-methoxybenzonitrile in the presence of potassium carbonate using the general procedure described. in Ex 1(a) to give 1-(4-cyano-2-methoxybenzyl)-6-nitroindole (W) in 78% yield as a solid, m.p. 190.5°-191° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[C:18]([N:17]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH:16][C:14]([C:10]1[O:9][CH:13]=[CH:12][CH:11]=1)=[O:15])([CH3:21])([CH3:19])[CH3:20]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccco1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)N(Cc1ccccc1)NC(=O)c1ccco1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.8 g), 1-furoyl-2-t-butyl hydrazine (2 g) and excess powdered potassium carbonate were stirred in dimethylformamide (50 ml) at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether and washed several times with water. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed in vacuo. The white solid product was chromatographed on silica gel (G:70-230 mesh) using methylene chloride as eluent to afford the product in good yield: m.p. 152-153.
Reaction SMILES: [CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][C:2]([N+:10]([O-:12])=[O:11])([CH3:9])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: COC(=O)CCC(C)(C)[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCO)[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 4-methyl-4-nitropentanoate (17.5 g, 0.1 mol) was dissolved in ethanol (200 ml) and cooled to 5° C., after which sodium borohydride (7.55 g, 0.2 mol) was added. The mixture was stirred at room temperature for 1 h, and at 50° C. for 3 h. Water (100 ml) and hydrochloric acid were added to adjust the pH to 3, and ethanol was evaporated by concentration under reduced pressure. The residue was extracted with ethyl acetate (250 ml) and water (100 ml) and washed with saturated brine. Ethyl acetate was evaporated by concentration under reduced pressure to give the objective compound (14.7 g, yield 91.2%).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43](=[O:56])[O:44][CH2:45][CH2:46][C:47]2[C:52]([CH3:53])=[CH:51][C:50](Br)=[CH:49][C:48]=2[CH3:55])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:42][C:43]([O:44][CH2:45][CH2:46][C:47]2[C:52]([CH3:53])=[CH:51][C:50]([B:25]([OH:27])[OH:26])=[CH:49][C:48]=2[CH3:55])=[O:56])[CH:34]=[CH:35][C:36]=1[S:37]([CH2:40][CH3:41])(=[O:39])=[O:38])#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(Br)cc2C)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CCS(=O)(=O)c1ccc(NC(=O)OCCc2c(C)cc(B(O)O)cc2C)cc1C#N
Yield: 54 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 32C (480 mg, 1.0 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 32D (240 mg, 54%) as a tan solid. MS (ESI) m/z 453.12 (M+Na)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][CH:22]1[CH2:27][NH:26][CH2:25][CH2:24][N:23]1[C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:26]2[CH2:25][CH2:24][N:23]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[CH:22]([CH3:21])[CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2C)c1

Procedure:
143 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 2-methyl-1-m-tolylpiperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: Cc1ccc(O)c(B(O)O)c1
Product: COc1cccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1O
Yield: 20 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-5-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenylboronic acid in 20% yield using method F; δH [2H6]-DMSO 13.57,(1H, b), 13.09,(1H, b), 8.33,(2H, t), 8.24,(2H, m), 8.15,(2H, m), 7.95,(1H, s), 7.70,(1H, d), 7.18,(1H, d), 7.10,(1H, d), 6.91,(2H, m), 3.84,)3H, s), 2.35,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.17 minutes.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH2:28][OH:29].C(N(CC)CC)C>CN(C=O)C>[CH3:22][C:23]1[N:24]([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[N:26][C:27]=1[CH2:28][OH:29]
Reactant: Cc1nc[nH]c1CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(CO)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 50.4 %

Procedure:
A solution of triphenylchloromethane (13.1 g) in dry DMF (80 ml) was added dropwise over 30 min. to a stirred solution of 4-methyl-5-imidazolemethanol hydrochloride (7.0 g) and triethylamine (9.52 g) in dry DMF (75 ml) at room temperature under nitrogen, and stirring was continued for 2.5 h. The suspension was poured onto ice (600 ml), stirred for 30 min. and filtered. The resulting solid (12.0 g) was triturated twice with acetone (2×250 ml) to give the title compound (8.4 g), t.l.c. (System A 94.5:5:0.5) Rf 0.19.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][C:13](=[O:15])[CH3:14]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)CSc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 104.5 %

Procedure:
To a stirred solution of 4-bromothiophenol (5.09 g, 26.9 mmol) in NaOH (1.08 g, 26.9 mmol) and water (32 ml) was added chloroacetone (2.17 ml, 27.3 mmol) and the mixture was stirred under nitrogen for 45 min before extracting with ether, washing with water, drying (Na2SO4) and evaporating in vacuo, leaving 6.89 g (100%) of the title compound as a white solid, δ (CDCl3) 2.27 (3H, s), 3.65 (2H, s), 7.20 (2H, d, J=8.5 Hz), 7.41 (2H, d, J=8.5 Hz).
Reaction SMILES: C([Li])CCC.[CH:6]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:8])[CH3:7].[CH3:19][O:20][CH:21]1[O:25][C:24](=[O:26])[CH:23]=[CH:22]1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([S:9]([C:6]([CH:22]2[CH:21]([O:20][CH3:19])[O:25][C:24](=[O:26])[CH2:23]2)([CH3:8])[CH3:7])(=[O:10])=[O:11])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Reactant: COC1C=CC(=O)O1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC1OC(=O)CC1C(C)(C)S(=O)(=O)c1ccc(C)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.3 ml of a cyclohexane solution of 1.95M of butyllithium was slowly added with stirring at -70° C. under an inert atmosphere to a mixture of 500 mg of isopropyl-p-tolyl sulfone and 10 ml of anhydrous tetrahydrofuran and the mixture was stirred at -70° C. for 30 minutes. A solution of 287 mg of 5-methoxy-2,5-dihydrofuran-2-one in 4 ml of tetrahydrofuran was added to the mixture over 10 minutes and the mixture was held at -70° C. for one hour and was then poured into aqueous monosodium phosphate solution at 0° C. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was crystallized from isopropyl ether to obtain 490 mg of trans dl 4-(2-p-toluenesulfonyl-prop-2-yl)-5-methoxy-tetrahydrofuran-2-one in the form of white crystals melting at 129° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9](C)[CH2:10][CH2:11][C@H:12]1[C@H:20]([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClC(OCC)=O.Cl>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:21][CH:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]1[CH2:11][CH2:10][NH:9][CH3:8]
Reactant: C[C@@H]1c2ccccc2N(c2ccccc2)[C@H]1CCN(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNCCC1C(C)c2ccccc2N1c1ccccc1

Procedure:
7.5 ml of triethylamine are added to a solution of 5.0 g of trans-2-(2-dimethylaminoethyl)-3-methyl-1-phenylindoline in 36 ml of toluene. 2.6 ml of ethyl chloroformate are added dropwise whilst refluxing the reaction mixture. After one and two hours 2.6 ml of ethyl chloroformate are again added. After a reaction time of 3 hours, cooling is effected and the reaction mixture is distributed between methylene chloride and dilute hydrochloric acid. After the mixture is washed with water and dried over sodium sulphate, the solvent is removed, whereupon the ethyl carbamate of the trans-3-methyl-2-(2-methylaminoethyl)-1-phenylindoline remains as a brown oil. 2. The latter is dissolved in 17 ml of n-butanol. 3.5 g of pulverized potassium hydroxide are added. The mixture is heated for 4 hours in an oil bath at 110°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[C:21](Cl)(=O)[CH2:22][CH2:23][CH2:24][CH3:25].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:21]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccc2)=NC1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2
Temperature: 125 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2 g of 7-bromo-2-hydrazino-5-phenyl-3H-[1,4]benzodiazepine in 60 ml of tetrahydrofuran cooled in an ice bath under a nitrogen atmosphere is added 0.87 ml of valeryl chloride dropwise over 3 min. After stirring for 2.5 hrs, the reaction mixture is then poured into 100 ml of water and aqueous sodium bicarbonate. A solid precipitate is then collected on a filter, washed with water and dried. The resulting residue is then dissolved in 25 ml of acetic acid, heated under a nitrogen atmosphere in an oil bath to 125° C. for 35 min, allowed to cool, and concentrated under reduced pressure. Crystallization of the residue from a mixture of methanol and water yields 0.88 g of title product with melting point 87°-90° C. and 0.41 g of title product with melting point 88°-90° C. as a monohydrate.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O>[S:25]([O:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 55 %

Procedure:
Into 50 ml of pyridine, was dissolved 2.95 g (16.9 mmoles) of 3-tert-butoxycarbonylamino-1-propanol. To this solution, while being cooled in ice under an argon atmosphere, was added dropwise over a period of 40 minutes a pyridine solution containing 3.36 g (17.7 mmoles) of p-toluenesulfonyl chloride. The mixture was left standing overnight at 7° C., admixed with a small quantity of water, and evaporated to dryness. The residue was dissolved in 200 ml of chloroform, washed successively with 5% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution, and water, then dried over anhydrous sodium sulfate, evaporated to dryness, and subjected to column chromatography using 120 g of silica gel (Wako Gel® C-200) and a toluene-ethyl acetate (8:1 by volume) mixture as a developing solvent. The Fraction Nos. 35 to 68 (each 15 ml in volume) were combined and evaporated to dryness to obtain 3.06 g (55% yield) of O-tosyl-3-tert-butoxycarbonylamino-1-propanol in the form of colorless oil.
Reaction SMILES: [OH-].[Na+].[NH3:3].[C:4]([OH:11])(=[O:10])/[CH:5]=[CH:6]/[C:7](O)=O.[CH2:12](O)[CH3:13]>>[NH2:3][C@H:5]([C:4]([OH:11])=[O:10])[C@H:6]([CH2:12][CH3:13])[CH3:7]
Reactant: CCO
Reactant: O=C(O)/C=C/C(=O)O
Reactant: N
Agent: [Na+]
Agent: [OH-]
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
On a pilot-plant scale the free amine is prepared by the addition of NaOH/NH3. Fumaric acid is dissolved in hot ethanol, the free amine is added dropwise, and (Ile-Thia)2 furmarate (M=520.71 gmol−1) precipitates. The analysis of isomers and enantiomers is carried out by electrophoresis.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30](CC=C)[C:28](=[O:29])[CH2:27][C@H:26](O)[C@@H:25]([CH3:39])[C@@H:24](/C(/C)=C/[C@H]2C[C@@H](OC)[C@H](O)CC2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2(O)[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.IC1C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:57][O:56][CH:4]1[CH:5]2[O:10][CH:9]([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH2:24][CH:25]([CH3:39])[CH2:26][CH2:27][C:28](=[O:29])[CH2:30][CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3]1
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1CC(C)CC(C)=CCC(=O)CCC(C)COC(=O)C2CCCCN2C(=O)C(=O)C2OC1C(OC)CC2C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of the FR-900506 substance (100.7 mg) in pyridine (3 ml) was added p-iodobenzenesulfonyl chloride (500 mg), and the mixture was stirred at room temperature for 36 hours. The solution was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure The residue was chromatographed on silica gel (developing solvent diethyl ether and hexane, 3:1 v/v) to give 17-allyl-1,14-dihydroxy-12-2-[4-(p-iodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (61 mg) and 17-allyl-1-hydroxy-12-[2-[4-(piodobenzenesulfonyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (12 mg), respectively.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)P(N(C)C)(N(C)C)=O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: CCCC[Sn](CCCC)(CCCC)Cc1ccccc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1(C)CC(=O)c2c(Cc3ccccc3)cn(-c3ccccn3)c2C1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (10 mg, 0.31 mmol), benzyltributylstannane (253 mg, 0.68 mmol) and dichlorobis(triphenylphosphine)palladium (50 mg, 0.08 mmol) in hexamethylphosphoramide (1 mL) was heated at 70° C. for 48 h. The mixture was cooled to room temperature, diluted with DCM (2 mL), and the solution chromatographed on silica gel, eluting with isohexane: EtOAc (4:1). The title compound (45 mg, 43%) was isolated as a colourless solid. mp 111-113° C. Found: C, 79.7; H, 6.7; N, 8.3%. Calc. C22H22N2O: C, 79.97; H, 6.71; N, 8.48%. 1H NMR (360 MHz, CDCl3) δ 1.11 (6H,s), 2.39 (2H,s), 2.93 (2H,s), 4.17 (2H,s), 6.61 (1H,s), 7.16-7.34 (7H,m), 7.77 (1H, d of t, J=7.7 and 1.9 Hz), 8.50-8.53 (1H,m). MS (ES+) 331 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C[Al](C)C.[CH2:9]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:10][CH3:11]>ClCCl.C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:13]1[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[C:12]1[CH2:9][CH2:10][CH3:11])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCNC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Reaction time: 0.05 h

Procedure:
A solution of n-propylamine (3.0 mL, 36 mmol) in dichloromethane (75 mL) was cooled to 0° C.; trimethylaluminum (available as a 2 M solution in toluene, 18 mL, 36 mmol) was added dropwise with stirring over a period of three minutes. The reaction was stirred for one hour at 0° C. and 30 minutes at ambient temperature. A solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (5.80 g, 17.8 mmol, prepared as described in Parts A-D of Example 1) in dichloromethane (30 mL) was added, and the reaction was then heated at reflux for three days. The work-up procedure described in Part E of Example 1 was followed to provide N-propyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide as a brown oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N:13]=[C:14]=[O:15])[C:10]([F:12])=[CH:11][C:6]=2[S:5][C:4]1=[O:16])[CH3:2].C([N:19]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:20]1[C:21](O)=[O:22])C.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([N:13]3[C:21](=[O:22])[CH:20]4[CH2:24][CH2:25][CH2:26][CH2:27][N:19]4[C:14]3=[O:15])[C:10]([F:12])=[CH:11][C:6]=2[S:5][C:4]1=[O:16])[CH3:2]
Reactant: CCN1CCCCC1C(=O)O
Reactant: CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(=O)sc2cc(F)c(N3C(=O)C4CCCCN4C3=O)cc21
Yield: 52.3 %

Procedure:
3-Ethyl-6-fluoro-2(3H)-benzothiazolon-5-yl isocyanate (1.16 g) and ethyl pipecolic acid (1.07 g) were dissolved in toluene (5 ml). A catalytic amount of triethylamine was added thereto, and the resultant mixture was stirred at 25° C. for 12 hours. Water was added to the reaction mixture, which was then extracted with toluene. The extract was dried and concentrated to give 2-[3-ethyl-6-fluoro-2(3H)-benzothiazolon-5yl]tetrahydroimidazo[1,5-a]-pyridine-1,3(2H,5H)-dione (0.89 g). m.p., 162°-164° C.